Atrophic vaginitis is a hormone-dependent disease involving the lower urinary tract, genital tract, and pelvic floor. Generally, atrophic vaginitis becomes evident during or after menopause, the symptoms increasing with age. Symptoms relating to urogenital aging are due to estrogen loss from follicular depletion in the menopausal ovary. This estrogen loss accounts for the majority of the anatomical, cytological, bacteriologic, and physiologic genital changes that occur in the vagina.
With estrogen loss, the vagina shortens, narrows, and the vaginal walls become thinner, less elastic and pale in color. As a result, numerous symptoms begin to appear. Collectively, the vaginal symptom complex is referred to as atrophic vaginitis. Unlike vasomotor symptoms, atrophy-related problems such as dyspareunia, burning and chronic vaginitis do not disappear with time. Irritation and burning are frequently a result of a chronic discharge caused by pH elevations and bacteriologic changes of the vaginal vault. Itching, which often interferes with a restful sleep, is also due to thinning and inflammation of the vulvovaginal epithelial layer. The vaginal surface thus becomes friable, with petechiae, ulcerations, and bleeding often occurring after minimal trauma.
The most common vaginal atrophy symptom is vaginal dryness. A survey of 1,200 Swedish menopausal women randomly selected from a birth cohort indicated that half reported some type of vaginal or urogenital symptom, the most common being vaginal dryness and associated dyspareunia (Iosif et al., Acta Obstetricia et Gynaecologica Scandinnavica 1984; 63: 257-60). Vaginal dryness can be bothersome to sexually abstinent women, but it is voiced as the most bothersome problem in sexually active women who find coital activity uncomfortable because of inadequate lubrication (Bachmann et al., Maturitas 1984; 6: 19-29). Vaginal dryness has not only been associated with painful intercourse, but also a decrease in libido (Bachmann et al., Maturitas 1985; 7: 211-216). Vaginal dryness is not limited to menopausal women; up to 15% of women who are still menstruating also report dyspareunia and dryness (Oldenhave, Well-Being and Sexuality in the Climacteric: A Survey Based on 6,622 Women [dissertation]. Leidshendam, United Kingdom: Excelsior; 1991).
It has been suggested that about 50% of otherwise healthy women over 60 years of age have symptoms related to vaginal atrophy (Iosif et al., Acta Obstetricia et Gynaecologica Scandinnavica 1984; 63: 257-60). Overall, in about 45% of menopausal women vaginal atrophy can be clinically manifest as a syndrome of vaginal dryness, itching, irritation and dyspareunia (Bygdeman et al., Maturitas 1996; 23: 259-63). The vaginal symptoms range in severity from annoying to debilitating. In the United States, 20 million women, who do not undergo estrogen hormone therapy, will have socially disabling symptoms related to urogenital atrophy (Samsioe, Am J Obstet Gynecol 1998; 178: S245-S249).
Estrogen replacement therapy has been for many years the basis of drug therapy for the maintenance of menopausal urogenital health. However, it is well known that estrogen induces cell proliferation in mammary gland epithelium (Jordon, V C, Scientific American 1998: 60-67). Notably, as early as 12 months, the percentage of women with density grade increases was 0% in the placebo group and 3.5% in the estrogen alone group (Greendale G A et al., Ann Intern Med 1999; 130: 262-9). Overall, estrogen has long been implicated as the main sex hormone in the initiation and promotion of breast cancer. The case against estrogen has been well documented (Hulka et al. Lancet 1995, 346: 883-997; Early breast cancer trialists collaborative group, Lancet 1992; ii: 1-15; Early breast cancer trialists collaborative group, Lancet 1992, ii: 71-85; Haddow et al., British Medical Journal 1944 (September 23): 4368-4373; Henderson et al., Cancer Research 1988, 48: 246-253).
In contrast, continuous large doses of progesterones have been shown to be as effective as tamoxifen when given to women with advanced breast cancer (Rose et al., Hormone Research 1989, 32 (Suppl 1): 189-197). Progesterone appears to have no effect on quiescent breast cells (Clark et al., Endocrinology Reviews 1990, 11(2): 266-301). Progesterone has also been shown to inhibit the production of cathepsin-D, a protein that is mitogenic and could play a role in tumor invasion (Clark et al., Endocrinology Reviews 1990; 11(2): 266-301).
Removal of the ovaries or administration of an anti-estrogenic drug has been a major therapeutic option in breast cancer-risk patients. The removal of estrogen has a negative impact on a women's health, increasing the risk for osteoporosis and impeding urogenital health. For women after treatment of breast cancer, menopausal symptoms will be so severe that consideration must be given to using some form of hormonal therapy. Thus, the search for menopausal therapies, which preserve estrogen's potential benefits while avoiding undesirable estrogen effects in breast tissue, has led to the development of compounds known as selective estrogen receptor modulators (SERMs). The SERMs represent a structurally diverse group of non-steroidal compounds that can evoke either estrogen-like (agonist) or estrogen-blocking (antagonist) responses that vary by cell type and tissue.
The most successful SERM to date is tamoxifen (available commercially from Astra-Zeneca as Nolvadex®), which is a triphenylethylene derivative. Tamoxifen demonstrates antiestrogenic effects through its ability to compete with estrogen for binding sites in target tissue such as breast tissue (Fisher et al., N Engl J Med 1989; 320: 479-84). Tamoxifen is widely used for the treatment of hormone-responsive breast cancer (Osborne C K, N Engl J Med 1998; 339: 1609-18). Specifically, tamoxifen is indicated for the treatment of metastatic breast cancer, for the use of adjuvant therapy for the treatment of localized breast cancer, and for the reduction of risk of breast cancer in high-risk women (Mitlak et al., Drugs 1999; 57: 653-663).
Tamoxifen has been shown to act as an agonist in uterine tissue (Barakat R R, Cancer Treat Res 1998; 94: 195-207). Tamoxifen stimulates uterine epithelial cell proliferation, increasing the risk of uterine cancer four-fold in women over 50 years of age, thus limiting its utility in treating healthy postmenopausal women (Fisher et al., J Natl Cancer Inst 1998; 90: 1371-88). Since, uterine safety is of concern to women who are considering therapy for breast cancer, the use of tamoxifen has been cautioned in non-hysterectomized patients. Overall, the ACOG continues to recommend concomitant progestin for women receiving an estrogen agonist regimen (American College of Obstetricians and Gynecologists, Hormone replacement therapy. ACOG technical bulletin no. 93. Washington, D.C.: American College of Obstetricians and Gynecologists, 1992). The Food and Drug Administration (FDA) has imposed a black box warning on all FDA approved unopposed estrogens stating the following: “The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.” The FDA has imposed a similar black box warning on tamoxifen with regards to the increased risk of endometrial cancer.
The mechanism by which SERMs can exert both estrogen agonist and estrogen antagonist effects in a tissue-selective manner is not completely understood, but recent advances in this field have shed much light on this complex issue. Both estrogens and SERMs regulate genes through a series of molecular events that occur subsequent to their binding the intracellular estrogen receptor (Siris et al., Selective estrogen receptor modulators. The Aging Skeleton. San Diego, Calif.: Academic Press, 1999, Ch 42: 507-20). There are two types of estrogen receptors that have been identified to date: ER-alpha and ER-beta. Both types of estrogen receptors have two transcriptional activation domains, Activation Factor-1 (AF-1) and Activation Factor-2 (AF-2). Activation of a domain will regulate the level of DNA transcriptional activity. For example, tamoxifen will bind to uterine ER-alpha and stimulate AF-1 activity, but AF-2 activity is inhibited (Smith et al., Molecular Endocrinology 1997; 11: 657-666; McDonnell D., Trends in Endocrinology and Metabolism 1999; 10: 301-311). Further, the action of tamoxifen upon cell cycle machinery in the uterine epithelium is similar to that observed upon estradiol stimulation; tamoxifen induces a wave of DNA synthesis in uterine epithelial with kinetics similar to those seen after estradiol treatment (Hart J E, Pharmacol Ther. 1990; 47: 203-18). The AF-1 transcriptional activation domain of the estrogen receptor that is activated both by estradiol and tamoxifen binding to this receptor regulates the response seen in the uterus (Zhang et al., Journal of Endocrinology 2005; 184: 129-140).
Both ER-alpha and ER-beta are found in the vaginal epithelium. The expression of ER-alpha, and not ER-beta, in menopausal women has been regulated by estrogen replacement therapy. In menopausal patients, ER-alpha has been detected significantly more frequently in the vaginal walls of estrogen treated patients than in those who were untreated (Rezapour et al., Int Urogyncol J Pelvic Floor Dysfunct 2003; 14 (4): 276-81). Specifically, ER-alpha was detected in the vaginal epithelial, stromal and smooth muscle cells, but was not observed in vaginal blood vessels. ER-beta was detected in epithelial and vascular smooth muscle cells of the vagina. Expression of ER-beta markedly declines in menopause, regardless of estrogen replacement therapy (Gebhart J B et al., Am J Obstste Gynecol 2001; 185: 1325-30).
There is currently only one approved method for the treatment of atrophic vaginitis, and that is the administration of exogenous estrogens. Further, FDA guidance states that vaginal products should be considered for the treatment of symptoms of vulvar and vaginal atrophy associated with the menopause when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy (See Guidance For Industry: Labeling Guidance for Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Prescribing Information for Health Care Providers and Labeling, available at http://www.fda.gov/cder/guidance/index.htm). Yet, the FDA has imposed a warning on all FDA approved estrogens stating the following:                (Trade name) should not be used in women with any of the following conditions: known, suspected, or history of cancer of the breast.(See Guidance For Industry: Labeling Guidance for Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Prescribing Information for Health Care Providers and Labeling, available at http://www.fda.gov/cder/guidance/index.htm). Overall, many women fear the increase risk of developing breast cancer with estrogen replacement therapy. Thus, while estrogen therapy is effective in treating atrophic vaginitis, there is poor patient compliance. Furthermore, there is no approved method for the treatment of atrophic vaginitis in breast cancer risk patients. There is no approved vaginal administered method for the treatment of atrophic vaginitis with the use of triphenylethylene derivatives. There is no approved vaginal administered method for the treatment of atrophic vaginitis with the use of triphenylethylene derivatives in combination with progesterone to be used in non-hysterectomized women.        
Thus, there is a clear need in the art to provide an effective and safe vaginally administered therapy to treat atrophic vaginitis in women who are unable or unwilling to take estrogen therapy due to increased breast cancer or other carcinogenic risk. Overall, a new method that would have the benefits of estrogens, and at the same time decrease the carcinogenic risks and side effects, is needed because the present methods are far from optimal. No drug candidate has emerged to fill the needs of women who have increased carcinogenic risks and who require the benefits of estrogen replacement to live productive lives.